Reduction of hair growth

ABSTRACT

Mammalian hair growth is reduced by applying an agonist of farnesoid X receptor.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.11/141,798, filed May 31, 2005, which is incorporated herein byreference in its entirety.

BACKGROUND

The invention relates to reducing hair growth in mammals, particularlyfor cosmetic purposes.

A main function of mammalian hair is to provide environmentalprotection. However, that function has largely been lost in humans, inwhom hair is kept or removed from various parts of the body essentiallyfor cosmetic reasons. For example, it is generally preferred to havehair on the scalp but not on the face.

Various procedures have been employed to remove unwanted hair, includingshaving, electrolysis, depilatory creams or lotions, waxing, plucking,and therapeutic antiandrogens. These conventional procedures generallyhave drawbacks associated with them. Shaving, for instance, can causenicks and cuts, and can leave a perception of an increase in the rate ofhair regrowth. Shaving also can leave an undesirable stubble.Electrolysis, on the other hand, can keep a treated area free of hairfor prolonged periods of time, but can be expensive, painful, andsometimes leaves scarring. Depilatory creams, though very effective,typically are not recommended for frequent use due to their highirritancy potential. Waxing and plucking can cause pain, discomfort, andpoor removal of short hair. Finally, antiandrogens—which have been usedto treat female hirsutism—can have unwanted side effects.

It has previously been disclosed that the rate and character of hairgrowth can be altered by applying to the skin inhibitors of certainenzymes. These inhibitors include inhibitors of 5-alpha reductase,ornithine decarboxylase, S-adenosylmethionine decarboxylase,gamma-glutamyl transpeptidase, and transglutaminase. See, for example,Breuer et al., U.S. Pat. No. 4,885,289; Shander, U.S. Pat. No.4,720,489; Ahluwalia, U.S. Pat. No. 5,095,007; Ahluwalia et al., U.S.Pat. No. 5,096,911; and Shander et al., U.S. Pat. No. 5,132,293.

Farnesoid X receptor (also known as “FXR”, “RIP14”, “bile acidreceptor”, “BAR”, “HRR1” and “NR1H4”) is a member of the family ofligand-activated transcription factors that bind to specific cis-actingregulatory elements in the promoters of their target genes and modulategene expression in response to ligands. Some of these receptors bind totheir target genes as dimers consisting of two molecules of the samereceptor homodimers), while others bind to as dimers consisting of onemolecule each of two different receptors (heterodimers). Farnesoid Xreceptor forms a heterodimer with the retinoid X receptor (RXR) andbinds to an inverted hexanucleotides repeat spaced by one nucleotide inthe promoters of its target genes. Farnesoid X receptor is activatedthrough interaction with ligands such as farnesoids and bile acids. Inaddition, coactivators (DRIP205/TRAP220, SRC-1 and PGC-1alpha) thatbridge between the ligand-activated farnesoid X receptors and the basaltranscription machinery, and/or influence the chromatin structure, canenhance the transcriptional activity of farnesoid X receptor.

Farnesoid X receptor helps maintain bile acid homeostasis by modulatingthe expression of genes involved in the synthesis and transport of bileacid. Bile acids are the end product of cholesterol catabolism.Synthesis of bile acid is the predominant mechanisms for the excretionof excess cholesterol. Most bile acids in human are chenodeoxycholicacid, cholic acid, deoxycholic acid, ursodeoxycholic acid andlithocholic acid. While the level of bile acids is increased, farnesoidX receptor is activated and upregulates the expression of the bile saltexport pump that is responsible for bile acid excretion. In addition tobile acid excretion, bile acid-activated farnesoid X receptor repressesthe transcription of cholesterol 7alpha-hydroxylase (CYP7A1), which therate-limiting enzyme in the bile acid biosynthesis pathway.

SUMMARY

In one aspect, the invention provides a method (typically a cosmeticmethod) of reducing unwanted mammalian (preferably human) hair growth byapplying to the skin an agonist of farnesoid X receptor in an amounteffective to reduce hair growth. Preferably, the agonist interactsstrongly with the farnesoid X receptor. The unwanted hair growth may beundesirable from a cosmetic standpoint.

In another aspect, the invention provides a method of reducing unwantedmammalian hair growth by applying to the skin a compound selected fromthe group consisting of bile acids, analogs of bile acids, andderivatives of bile acids.

In another aspect, the invention provides a method of reducing unwantedmammalian hair growth by applying to the skin a compound selected fromthe group consisting of farnesoids, analogs of farnesoids, andderivatives of farnesoids.

In a another aspect, the invention provides a method of reducingunwanted mammalian hair growth by applying to the skin a compound thatincreases the formation of FXR-RXR heterodimer, the expression offarnesoid X receptor, or promotes coactivator recruitment andinteraction with FXR-RXR heterodimer.

In a further aspect, the invention provides a method of providing abenefit to exfoliated skin by applying any of the aboveagonists/compounds.

Typically, in practicing the aforementioned methods, theagonist/compound will be included in a topical composition along with adermatologically or cosmetically acceptable vehicle. Accordingly, thepresent invention also relates to topical compositions comprising adermatologically or cosmetically acceptable vehicle and an agonist offarnesoid X receptor. The present invention further relates to topicalcompositions comprising a dermatologically or cosmetically acceptablevehicle and (a) a compound selected from the group consisting of bileacids, analogs or derivatives of bile acids; (b) a compound selectedfrom the group consisting of farnesoids, analogs or derivatives offarnesoids; and/or (c) a compound that increases the formation ofFXR-RXR heterodimer, the expression of farnesoid X receptor, or promotescoactivator recruitment and interaction with FXR-RXR heterodimer.

In addition, the present invention relates to the use of an agonist offarnesoid X receptor for the manufacture of a therapeutic topicalcomposition for reducing hair growth. Further, the present inventionrelates to the use of a compound for the manufacture of a therapeutictopical composition for reducing hair growth, wherein the compound is(a) a compound that selected from the group consisting of bile acids,analogs or derivatives of bile acids; (b) a compound selected from thegroup consisting of farnesoids, analogs or derivatives of farnesoids;and/or (c) a compound that increases the formation of FXR-RXRheterodimer, the expression of farnesoid X receptor, or promotescoactivator recruitment and interaction with FXR-RXR heterodimer.

In some embodiments, the agonist/compound is not a carbomate or ester ofα-difluoromethylornithine. Carbamates, esters, and other conjugates ofα-difluoromethylornithine are described in U.S. Ser. No. 10/397,132,which was filed on Mar. 26, 2003, is owned by the same owner as thepresent application, and is hereby incorporated herein by reference.

“Agonist of farnesoid X receptor”, as used herein, means a compound thatactivates farnesoid X receptor.

An agonist that “interacts strongly” with the farnesoid X receptor isone that binds the receptor with such affinity that it elicits aresponse that is at least approximately comparable to (in magnitude) tothat elicited by farnesoids.

Specific compounds include both the compound itself andpharmacologically acceptable salts of the compound.

Other features and advantages of the invention may be apparent from thedetailed description and from the claims.

DETAILED DESCRIPTION

An example of a preferred composition includes at least one agonist offarnesoid X receptor in a cosmetically and/or dermatologicallyacceptable vehicle. The composition may be a solid, semi-solid, orliquid. The composition may be, for example, a cosmetic and dermatologicproduct in the form of an, for example, ointment, lotion, foam, cream,gel, or solution. The composition may also be in the form of a shavingpreparation, an aftershave or an antiperspirant. The vehicle itself canbe inert or it can possess cosmetic, physiological and/or pharmaceuticalbenefits of its own.

Examples of agonists of farnesoid X receptor include bile acids,farnesoids, their analogs and derivatives, and other compounds.

Derivatives and analogs of bile acids are known. For example, J. Med.Chem. (2004), 47, 4559-4569 describes bile acid derivatives. J. Biol.Chem. (2004), 279(10), 8856-8861. describes various bile acids.Derivatives and analogs of farnesoids are known. For example, U.S. Pat.No. 6,187,814 describes farnesoid derivatives. Other examples ofagonists of farnesoid X receptor are disclosed in WO2004007521,WO03015771, WO2004048349, WO03076418, WO2004046162, WO03060078,WO02072598, WO03080803, WO2003086303, WO 2004046068, U.S. Pat.20030187042, U.S. Pat. 0040176426, U.S. Pat. 20040180942, U.S. Pat. No.6,452,032, U.S. Pat. 2003203939, U.S. Pat. 2005004165, J. med. Chem.(2000), 43(6), 2971-2974, Mol. Gen. Met. (2004), 83, 184-187, Drugs forthe future 91999), 24(4), 431-438, Current Pharmaceutical Design (2001),7, 231-259. Examples of coactivators involved in FXR-RCR hetrodimer aredisclosed in Genes & Dev. (2004), 18, 157-169 and J. Biol. Chem. (2004),279(35), 36184-36191. All of these references are incorporated byreference.

Specific examples of agonists of farnesoid X receptor are provided inTables I.

TABLE I Examples of Farnesoid X receptor agonists Farnesol FarnesalFarnesyl acetate Farnesoic acid Methyl farnesyl ether Methyl farnesoateEthyl farnesyl ether Ethyl farnesoate7-Methyl-9-(3,3-dimethyloxivanyl)-3-methyl-2,6-nonadienoic acid methylester (also known as Juvenile hormone III) Lithocholic acid Cholic acidDeoxycholic acid Chenodeoxycholic acid Ursodeoxycholic acid6-alpha-Ethyl chenodeoxycholic acid Benzenesulfonamide,N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-(also known as T0901317)Benzoic acid,3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]-(also known as GW4064) Phosphonicacid, [[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-,tetraethyl ester (also known asSR-12813) Phosphonic acid, [2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethylidene]bis-,tetrakis(1-methylethyl) ester (also knownas SR-45023A or apomine) Phosphonic acid,[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethylidene]bis-,tetraethyl ester (also known as SR-9213)Phosphonic acid, [[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-,tetrakis(1-methylethyl) ester (alsoknown as SR-12823i)7-Methyl-9-(3,3-dimethyloxivanyl)-3-methyl-2,6-nonadienoic acid ethylester 3α,7α-dihydroxy-6α-ethyl-5p-cholan-24-oic acid3α,7α-dihydroxy-6α-propyl-5p-cholan-24-oic acid3α,7α-dihydroxy-6α-allyl-5p-cholan-24-oic acid

The composition may include more than one agonist of farnesoid Xreceptor. In addition, the composition may include one or more othertypes of hair growth reducing agents, such as those described in U.S.Pat. No. 4,885,289; U.S. Pat. No. 4,720,489; U.S. Pat. No. 5,132,293;U.S. Pat. No. 5,096,911; U.S. Pat. No. 5,095,007; U.S. Pat. No.5,143,925; U.S. Pat. No. 5,328,686; U.S. Pat. No. 5,440,090; U.S. Pat.No. 5,364,885; U.S. Pat. No. 5,411,991; U.S. Pat. No. 5,648,394; U.S.Pat. No. 5,468,476; U.S. Pat. No. 5,475,763; U.S. Pat. No. 5,554,608;U.S. Pat. No. 5,674,477; U.S. Pat. No. 5,728,736; U.S. Pat. No.5,652,273; WO 94/27586; WO 94/27563; and WO 98/03149, all of which areincorporated herein by reference.

The concentration of the agonist in the composition may be varied over awide range up to a saturated solution, preferably from 0.1% to 30% byweight or even more; the reduction of hair growth increases as theamount of agonist applied increases per unit area of skin. The maximumamount effectively applied is limited only by the rate at which theagonist penetrates the skin. The effective amounts may range, forexample, from 10 to 3000 micrograms or more per square centimeter ofskin.

The vehicle can be inert or can possess cosmetic, physiological and/orpharmaceutical benefits of its own. Vehicles can be formulated withliquid or solid emollients, solvents, thickeners, humectants and/orpowders. Emollients include stearyl alcohol, mink oil, cetyl alcohol,oleyl alcohol, isopropyl laurate, polyethylene glycol, petroleum jelly,palmitic acid, oleic acid, and myristyl myristate. Solvents includeethyl alcohol, isopropanol, acetone, diethylene glycol, ethylene glycol,dimethyl sulfoxide, and dimethyl formamide.

The composition optionally can include components that enhance thepenetration of the agonist into the skin and/or to the site of action.Examples of penetration enhancers include urea, polyoxyethylene ethers(e.g., Brij-30 and Laureth-4),3-hydroxy-3,7,11-trimethyl-1,6,10-dodecatriene, terpenes, cis-fattyacids (e.g., oleic acid, palmitoleic acid), acetone, laurocapram,dimethylsulfoxide, 2-pyrrolidone, oleyl alcohol, glyceryl-3-stearate,propan-2-ol, myristic acid isopropyl ester, cholesterol, and propyleneglycol. A penetration enhancer can be added, for example, atconcentrations of 0.1% to 20% or 0.5% to 5% by weight.

The composition also can be formulated to provide a reservoir within oron the surface of the skin to provide for a continual slow release ofthe agonist. The composition also may be formulated to evaporate slowlyfrom the skin, allowing the agonist extra time to penetrate the skin.

A topical cream composition containing an agonist of farnesoid Xreceptor may be prepared by mixing together water and all water solublecomponents in a mixing vessel-A. The pH is adjusted in a desired rangefrom about 3.5 to 8.0. In order to achieve complete dissolution ofingredients the vessel temperature may be raised to up to 45° C. Theselection of pH and temperature will depend on the stability of theagonist. The oil soluble components, except for the preservative andfragrance components, are mixed together in another container (B) andheated to up to 70° C. to melt and mix the components. The heatedcontents of vessel B are poured into the water phase (container A) withbrisk stirring. Mixing is continued for about 20 minutes. Thepreservative components are added at temperature of about 40° C.Stirring is continued until the temperature reaches about 25° C. toyield a soft cream with a viscosity of 8,000-12,000 cps, or a desiredviscosity. The fragrance components are added at about 25° C.-30° C.while the contents are still being mixed and the viscosity has not yetbuilt up to the desired range. If it is desired to increase theviscosity of the resulting emulsion, shear can be applied using aconventional homogenizer, for example a Silverson L4R homogenizer with asquare hole high sheer screen. The topical composition can be fabricatedby including the agonist in the water phase during formulationpreparation or can be added after the formulation (vehicle) preparationhas been completed. The agonist can also be added during any step of thevehicle preparation. The components of come cream formulations aredescribed in the examples below.

EXAMPLE # 1 Cream

INCI Name W/w (%) DI Water 61.00-75.00 Agonist of farnesoid X receptor 1.00-15.00 Mineral oil 1.90 Glyceryl stearate 3.60 PEG 100 stearate3.48 Cetearyl alcohol 2.59 Ceteareth-20 2.13 Dimethicone, 100 ct 0.48Lipidure PMB^(a) 3.00 Advanced moisture complex^(b) 5.00 Stearyl alcohol1.42 Preservative, fragrance and color pigment qs Total 100.00^(a)polyquartinium-51 (Collaborative Labs, NY); ^(b)glycerin and waterand sodium PCA and urea and trehalose and polyqauternium-51 and sodiumhyaluronate (Collaborative Labs, NY)

EXAMPLE # 2 Cream

INCI Name w/w (%) Agonist of farnesoid X receptor  0.5-15.00 Glycerol(glycerin) 0-5 Isoceteth-20 3-7 Glyceryl isostearate 1.5-5   Dicaprylylether  3-15 Glyceryl triacetate (triacetin) 0.5-10  Preservative,fragrance and color pigment q.s. Water q.s. to 100.00

EXAMPLE # 3 Cream

INCI Name w/w (%) Agonist of farnesoid X receptor  0.5-15.00 Glycerol(glycerin) 0-5 Isoceteth-20 3-7 Glyceryl isostearate 1.5-5   Dicaprylylether  3-15 1-dodecyl-2-pyrrolidanone  0.5-10% Preservative, fragranceand color q.s. Water to 100.00

EXAMPLE #4 Cream

INCI Name w/w (%) Water 70 Glyceryl stearate 4 PEG-100 4 Cetearylalcohol 3 Ceteareth-20 2.5 Mineral oil 2 Stearyl alcohol 2 Dimethicone0.5 Preservatives 0.43 1-Dodecyl-2-pyrrolidanone 1-10 Total 100.00An agonist of farnesoid X receptor is added to the example 4 formulationand mixed until solubilized.

EXAMPLE 5 Cream

INCI Name w/w (%) Water 70-80 Glyceryl stearate 4 PEG-100 4 Cetearylalcohol 3 Ceteareth-20 2.5 Mineral oil 2 Stearyl alcohol 2 Dimethicone0.5 Preservatives 0.43 Monocaprylate/Caprate (Estol 3601, Uniquema, NJ) 1-10 Total 100.00An agonist of farnesoid X receptor is added to the example 5 formulationand mixed until solubilized.

EXAMPLE 6 Cream

INCI Name w/w (%) Water 70-80 Glyceryl stearate 4 PEG-100 4 Cetearylalcohol 3 Ceteareth-20 2.5 Mineral oil 2 Stearyl alcohol 2 Dimethicone0.5 Preservatives 0.43 cis Fatty acids  1-10 Total 100.00An agonist of farnesoid X receptor is added to the example 6 formulationand mixed until solubilized.

EXAMPLE 7 Cream

INCI Name w/w (%) Water 70-80% Glyceryl stearate 4 PEG-100 4 Cetearylalcohol 3 Ceteareth-20 2.5 Mineral oil 2 Stearyl alcohol 2 Dimethicone0.5 Preservatives 0.43 Terpene(s) 1-10  Total 100.00An agonist of farnesoid X receptor is added to the example 7 formulationand mixed until solubilized.

EXAMPLE 8 Cream

INCI Name w/w (%) Water 70-80% Glyceryl stearate 4 PEG-100 4 Cetearylalcohol 3 Ceteareth-20 2.5 Mineral oil 2 Stearyl alcohol 2 Dimethicone0.5 Preservatives 0.43 Polyoxyethylene sorbitans (tween) 1-10  Total100.00An agonist of farnesoid X receptor is added to the example 8 formulationand mixed until solubilized.

A hydroalcoholic formulation containing an agonist of farnesoid Xreceptor is prepared by mixing the formulation components in a mixingvessel. The pH of the formulation is adjusted to a desired value in therange of 3.5-8.0. The pH adjustment can also be made to cause completedissolution of the formulation ingredients. In addition, heating can beapplied to up to 45° C., or even up to 70° C. depending on the stabilityof the agonist to achieve dissolution of the formulation ingredients.The components of two hydroalcoholic formulations are listed below.

EXAMPLE #9 Hydro-Alcoholic

INCI Name w/w (%) Water 48.00-62.50 An agonist of farnesoid X receptor 0.5-15.00 Ethanol 16.00 Propylene glycol 5.00 Dipropylene glycol 5.00Benzyl alcohol 400 Propylene carbonate 2.00 Captex-300^(a) 5.00 Total100.00 ^(a)caprylic/capric triglyceride (Abitec Corp., OH).

EXAMPLE #10 Hydro-Alcoholic

INCI Name w/w (%) Water 53.00-67.9  An agonist of farnesoid X receptor 0.1-15.00 Ethanol 16.00 Propylene glycol 5.00 Dipropylene glycoldimethyl ether 5.00 Benzyl alcohol 4.00 Propylene carbonate 2.00 Total100.00

EXAMPLE #11 Hydro-Alcoholic

INCI Name w/w (%) Ethanol (alcohol) 80 Water 17.5 Propylene glycoldipelargonate 2.0 Propylene glycol 0.5 Total 100.00An agonist of farnesoid X receptor is added to the example 11formulation and mixed until solubilized.

The composition should be applied topically to a selected area of thebody from which it is desired to reduce hair growth. For example, thecomposition can be applied to the face, particularly to the beard areaof the face, i.e., the cheek, neck, upper lip, and chin. The compositionalso may be used as an adjunct to other methods of hair removalincluding shaving, waxing, mechanical epilation, chemical depilation,electrolysis and laser-assisted hair removal. Other actions that maketheir concept appearance are concurrent skin benefits in addition tohair reduction.

The composition can also be applied to the legs, arms, torso or armpits.The composition is suitable, for example, for reducing the growth ofunwanted hair in women. In humans, the composition should be appliedonce or twice a day, or even more frequently, to achieve a perceivedreduction in hair growth. Perception of reduced hair growth could occuras early as 24 hours or 48 hours (for instance, between normal shavingintervals) following use or could take up to, for example, three months.Reduction in hair growth is demonstrated when, for example, the rate ofhair growth is slowed, the need for removal is reduced, the subjectperceives less hair on the treated site, or quantitatively, when theweight of hair removed (i.e., hair mass) is reduced.

Human Hair Follicle Growth Assay:

Human hair follicles in growth phase (anagen) were isolated fromface-lift tissue (obtained from plastic surgeons) under dissecting scopeusing a scalpel and watchmakers forceps. The skin was sliced into thinstrips exposing 2-3 rows of follicles that could readily be dissected.Follicles were placed into 0.5 ml William's E medium (Life Technologies,Gaithersburg, Md.) supplemented with 2 mM L-glutamine, 10 μg/ml insulin,10 ng/ml hydrocortisone, 100 units of penicillin, 0.1 mg/ml streptomycinand 0.25 μg/ml amphotericin B. The follicles were incubated in 24-wellplates (1 follicle/well) at 37° C. in an atmosphere of 5% CO₂ and 95%air. Compounds are dissolved into dimethyl sulfoxide as 100-fold stocksolution. The control hair follicles were treated with dimethylsulfoxide without prostaglandin. The follicles were photographed in the24-well plates under the dissecting scope at a power of 10×. Typically,image recordings were made on day 0 (day follicles were placed inculture), and again on day 7. The length of hair follicle was assessedusing an image analysis software system. The growth of hair fiber wascalculated by the subtracting the follicle length on day 0 from thatdetermined on day 7.

Hamster Hair Mass Assay:

Hamster hair mass was determined using a method similar to thatdescribed in previous patent (US2004/0198821).

The agonists of farnesoid X receptor demonstrated a significantreduction of human hair follicle growth. All of the six agonists offarnesoid X receptor tested significantly reduced hair growth. Theresults are provided in Table II. The hair growth inhibition profile bythe agonists of farnesoid X receptor was found to be dose-dependent. Theresults are provided in Table III.

TABLE II Inhibition of human hair follicle growth by the agonists offarnestoid X receptor. Dose Hair follicle length increase (mm) FXRagonists (μM) Treated Control % Inhibition Deoxycholic acid 100 0.06 ±0.05 1.07 ± 0.14 94.3 ± 4.7 Ursodeoxycholic 200 0.20 ± 0.11 1.07 ± 0.14 81.3 ± 10.3 acid Chenodeoxycholic 100 0.05 ± 0.06 1.07 ± 0.14 95.3 ±5.6 acid Lithocholic acid 50 0.02 ± 0.02 1.07 ± 0.14 98.1 ± 1.9 Farnesol100 0.04 ± 0.07 0.87 ± 0.23 95.4 ± 8.0 Juvenile 100 0.21 ± 0.15 0.87 ±0.23  75.9 ± 17.2 hormone III

TABLE III Dose-dependent reduction of human hair follicle growth by theagonists of farnestoid X receptor. Dose Growth of follicle (mm) FXRagonists (μM) Treated Control % Reduction Deoxycholic acid 10 1.20 ±0.49 1.76 ± 0.36 31.8 ± 18.1 50 0.54 ± 0.34 1.76 ± 0.36 69.3 ± 13.6 1000.54 ± 0.34 1.76 ± 0.36 69.3 ± 13.6 Ursodeoxycholic acid 50 1.12 ± 0.241.76 ± 0.36 36.3 ± 13.6 100 0.86 ± 0.20 1.76 ± 0.36 51.1 ± 11.4 150 0.61± 0.20 1.76 ± 0.36 65.3 ± 11.4 Chenodeoxycholic 5 1.53 ± 0.29 1.55 ±0.02  1.3 ± 18.7 acid 25 0.79 ± 0.27 1.55 ± 0.02 49.0 ± 17.4 50 0.13 ±0.10 1.55 ± 0.02 91.6 ± 6.5  Lithocholic acid 2 0.82 ± 0.14 1.24 ± 0.2333.9 ± 11.3 10 0.44 ± 0.16 1.24 ± 0.23 64.5 ± 12.9 20 0.03 ± 0.06 1.24 ±0.23 97.6 ± 4.8 

Furthermore, the agonists of farnestoid X receptor were tested in thehamster hair mass assay. The agonists reduced hair mass in vivo as shownin Table IV.

TABLE IV Reduction of hamster hair mass by the agonists of farnestoid Xreceptor. Dose Hair mass (mg) FXR agonists (w/v) Vehicle* TreatedControl % Inhibition Lithocholic acid 4% ethanol 1.01 ± 0.12 1.96 ± 0.1946.4 ± 6.0 Chenodeoxycholic acid 5% ethanol 0.54 ± 0.08 2.28 ± 0.19 76.4± 2.6 Deoxycholic acid 5% ethanol 0.92 ± 0.14 2.66 ± 0.28 63.6 ± 6.0Ursodeoxycholic acid 5% ethanol 1.02 ± 0.16 2.43 ± 0.31 56.8 ± 3.8 *Thevehicle contains 90% ethanol and 10% propylene glycol.

Accordingly, other embodiments are within the scope of the followingclaims.

1. A method of reducing mammalian hair growth which comprises selectingan area of skin from which reduced hair growth is desired; and applyingto said area of skin a dermatologically acceptable compositioncomprising an agonist of farnesoid X receptor in an amount effective toreduce hair growth, wherein said agonist is not a carbamate or ester ofα-difluoromethylornithine and farnesol.
 2. The method of claim 1,wherein said agonist is a bile acid.
 3. The method of claim 1, whereinsaid agonist is an analog of a bile acid.
 4. The method of claim 1,wherein said agonist is a derivative of a bile acid.
 5. The method ofclaim 1, wherein said agonist interacts strongly with the farnesoid Xreceptor.
 6. The method of claim 1, wherein said agonist is lithocholicacid.
 7. The method of claim 1, wherein said agonist is cholic acid. 8.The method of claim 1, wherein said agonist is deoxycholic acid.
 9. Themethod of claim 1, wherein said agonist is chenodeoxycholic acid. 10.The method of claim 1, wherein said agonist is ursodeoxycholic acid. 11.The method of claim 1, wherein said agonist is 6-alpha-ethylchenodeoxycholic acid.
 12. The method of claim 1, wherein said agonistis a farnesoid.
 13. The method of claim 1, wherein said agonist is ananalog of a farnesoid.
 14. The method of claim 1, wherein said agonistis a derivative of a farnesoid.
 15. The method of claim 1, wherein saidagonist is farnesol.
 16. The method of claim 1, wherein said agonist isfarnesal.
 17. The method of claim 1, wherein said agonist is farnesylacetate.
 18. The method of claim 1, wherein said agonist is farnesoicacid
 19. The method of claim 1, wherein said agonist is methyl farnesylether.
 20. The method of claim 1, wherein said agonist is methylfarnesoate.
 21. The method of claim 1, wherein said agonist is ethylfarnesyl ether.
 22. The method of claim 1, wherein said agonist is ethylfarnesoate.
 23. The method of claim 1, wherein said agonist is7-methyl-9-(3,3-dimethyloxivanyl)-3-methyl-2,6-nonadienoic acid methylester (juvenile hormone III).
 24. The method of claim 1, wherein saidagonist is 7-methyl-9-(3,3-dimethyloxivanyl)-3-methyl-2,6-nonadienoicacid ethyl ester.
 25. The method of claim 1, wherein said agonist is3alpha,7alpha-dihydroxy-6alpha-ethyl-5p-cholan-24-oic acid.
 26. Themethod of claim 1, wherein said agonist is3alpha,7alpha-dihydroxy-6alpha-propyl-5p-cholan-24-oic acid.
 27. Themethod of claim 1, wherein said agonist is3alpha,7alpha-dihydroxy-6alpha-allyl-5p-cholan-24-oic acid.
 28. Themethod of claim 1, wherein said agonist is benzenesulfonamide,N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-.29. The method of claim 1, wherein said agonist is benzoic acid,3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]-.30. The method of claim 1, wherein said agonist is phosphonic acid,[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-,tetraethyl ester.
 31. The method of claim 1, wherein said agonist isphosphonic acid,[2-[3,5-bis(1-dimethylethyl)-4-hydroxyphenyl]ethylidene]bis-,tetrakis(1-methylethyl) ester.
 32. The method of claim 1, wherein saidagonist is phosphonic acid,[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethylidene]bis-,tetraethyl ester.
 33. The method of claim 1, wherein said agonist isphosphonic acid,[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-,tetrakis(1-methylethyl) ester.
 34. The method of claim 1, wherein theconcentration of said agonist in said composition is between 0.1% and30%.
 35. The method of claim 1, wherein the composition provides areduction in hair growth of at least 30% when tested in the Human HairFollicle assay.
 36. The method of claim 1, wherein the agonist isapplied to the skin in an amount of from 10 to 3000 micrograms of saidagonist per square centimeter of skin.
 37. The method of claim 1,wherein said area of skin is on the face of a human.
 38. The method ofclaim 37, wherein the composition is applied to the area of skin inconjunction with shaving.
 39. The method of claim 1, wherein said areaof skin is on a leg of the human.
 40. The method of claim 1, whereinsaid area of skin is on an arm of the human.
 41. The method of claim 1,wherein said area of skin is in an armpit of the human.
 42. The methodof claim 1, wherein said area of skin is on the torso of the human. 43.The method of claim 1, wherein said hair growth comprises androgenstimulated hair growth.
 44. The method of claim 1, wherein thecomposition further includes a second component that also causes areduction in hair growth.
 45. A method of reducing mammalian hairgrowth, which comprises selecting an area of skin including hairfollicles from which reduced hair growth is desired; and applying to thearea of skin a dermatologically acceptable composition comprising acompound selected from the group consisting of bile acids, bile acidanalogues, and bile acid derivatives in an amount effective to reducehair growth.
 46. A method of reducing mammalian hair growth, whichcomprises selecting an area of skin including hair follicles from whichreduced hair growth is desired; and applying to the area of skin, in anamount effective to reduce hair growth, a dermatogically acceptablecomposition comprising a compound, other than a carbamate or ester ofα-difluoromethylomithine and farnesol, selected from the groupconsisting of compounds that increase the formation of FXR-RXRheterodimer, compounds that promote coactivator recruitment andinteraction with FXR-RXR, and compounds that increase the expression offarnesoid X receptor.
 47. A method of reducing mammalian hair growth,which comprises selecting an area of skin from which reduced hair growthis desired; and applying to the area of skin a dermatologicallyacceptable composition comprising a compound selected from the groupconsisting of farsenoids, analogues of farsenoids, and derivatives offarsenoids in an amount effective to reduce hair growth.
 48. A method oftreating an area of exfoliated skin, comprising applying an agonist offarnesoid X receptor to the area of exfoliated skin.
 49. The method ofclaim 48, wherein the area of exfoliated skin has been shaved prior toapplication of the agonist of farnesoid X receptor.